Infection of inbred strains of mice with Leishmania major has correlated the outcome of disease with the capacity to stimulate the maturation of disparate subsets of CD4+ T cells, designated Th1 and Th2. Control of the parasite has been established when Th1 cells are generated, whereas progressive infection occurs with expansion of Th2. The inability of susceptible mice to heal is not due to a deletion in the T cell receptor repertoire, since several immunologic manipulations, including administration of antibodies to CD4 or IL-4, enable these mice to establish a Th1 response and heal infection. A comprehensive analysis of the CD4 cell repertoire that develops in healing and nonhealing mice revealed expansion of a common a/b+, CD+ population of cells that over-utilized the Va8, Vb4 heterodimeric T cell antigen receptor (TCR). These studies complement findings in various TCR transgenic mouse systems indicating that Th1 and Th2 cells arise from a common bipotential precursor. The L. major system thus offers an invaluable model for investigating signals that regulate the Th1/Th2 switch that has become increasingly implicated in the immune response to infectious agents. The goals of this proposal are to investigate these switch signals by a combination of in vivo and in vitro studies that focus on evolution of CD4 subset maturation within the context of intact animals infected with infectious organisms. Three specific aims are proposed: 1. to characterize the monokine profile generated during the interaction of infectious metacyclic promastigotes with host macrophages of various strains; 2. to characterize the cytokine milieu within tissues and lymph nodes at critical early periods following inoculation of infectious organisms; and 3. to use transgenic TCR mice expressing an immunodominant and highly conserved Leishmania-specific Vb4- Va8 TCR heterodimer to characterize the influence of these early signals on subsequent CD4+ subset development and to examine the functional status of cytokine genes unique to the Th1 or Th2 phenotype. Understanding the mechanisms that underlie CD4+ subset differentiation will not only contribute to fundamental insights toward leishmaniasis, but to the numerous infectious and autoimmune diseases in which this response has been documented. The implications for vaccine strategy are also substantial.